The invention relates to compounds capable of inhibiting the membrane type-1 metalloproteinase (MT1-MMP or MMP-14), and methods treating diseases such as cancer, heart and vascular disease, and arthritis using these compounds.
Breakdown and remodeling of the extracellular matrix (ECM) has been implicated in disease processes, including cancer, heart and vascular disease, and arthritis.
Cancer is a disease marked by the uncontrolled growth of abnormal cells. Cancer cells have overcome the barriers imposed in normal cells, which have a finite lifespan, to grow indefinitely. As the growth of cancer cells continue, genetic alterations may persist until the cancerous cell manifests an even more aggressive growth phenotype. If left untreated, metastasis, the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream, may ensue, destroying healthy tissue.
Cancer metastasis requires that the cancer cells leave the original tumor site, usually by entering the blood or lymphatic system, and spread to other regions of the body. Metastatic cells therefore must become free from the tissues in which they originally developed. This process can involve breakdown of ECM structures.
Arthritis also associated with changes in the ECM. In osteoarthritis, degradation of the ECM of articular cartilage occurs, resulting symptoms such as pain, stiffness, limited motion, tenderness, and swelling.
Changes in the ECM are also associated with cardiovascular diseases such as atherosclerosis, especially in the early stages of the disease.
Thus, new approaches to controlling changes in or degradation of the ECM are desirable.